U.S. patent number 8,821,409 [Application Number 13/141,908] was granted by the patent office on 2014-09-02 for lung aerosol collection device.
This patent grant is currently assigned to Georgia Tech Research Corporation, N/A, The United States of America as Represented by the Secretary of the Department of Health and Human Services, Centers for Disease. The grantee listed for this patent is Larry J. Anderson, Harris L. Bergman, David N. Ku, Prem A. Midha, Tamera Scholz. Invention is credited to Larry J. Anderson, Harris L. Bergman, David N. Ku, Prem A. Midha, Tamera Scholz.
United States Patent |
8,821,409 |
Ku , et al. |
September 2, 2014 |
Lung aerosol collection device
Abstract
A device for collecting material from lung aerosols. The device
functions by collecting aerosols from the lower airway separated
from material in the by collecting air from the upper airway in a
chamber that when full causes the remaining exhaled aerosols from
the lungs to be captured by a filter. The filter collects sample of
material from the separated lung aerosols.
Inventors: |
Ku; David N. (Decatur, GA),
Anderson; Larry J. (Atlanta, GA), Midha; Prem A. (Rolla,
MO), Bergman; Harris L. (Atlanta, GA), Scholz; Tamera
(Atlanta, GA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Ku; David N.
Anderson; Larry J.
Midha; Prem A.
Bergman; Harris L.
Scholz; Tamera |
Decatur
Atlanta
Rolla
Atlanta
Atlanta |
GA
GA
MO
GA
GA |
US
US
US
US
US |
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Assignee: |
The United States of America as
Represented by the Secretary of the Department of Health and Human
Services, Centers for Disease Control and Prevention
(Washington, DC)
N/A (Atlanta, GA)
Georgia Tech Research Corporation (N/A)
|
Family
ID: |
42288396 |
Appl.
No.: |
13/141,908 |
Filed: |
December 21, 2009 |
PCT
Filed: |
December 21, 2009 |
PCT No.: |
PCT/US2009/068961 |
371(c)(1),(2),(4) Date: |
September 13, 2011 |
PCT
Pub. No.: |
WO2010/075265 |
PCT
Pub. Date: |
July 01, 2010 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20120004571 A1 |
Jan 5, 2012 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61140292 |
Dec 23, 2008 |
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Current U.S.
Class: |
600/562; 600/543;
600/532; 600/529 |
Current CPC
Class: |
A61B
5/082 (20130101); A61B 5/097 (20130101); G01N
33/497 (20130101); A61B 2010/0087 (20130101) |
Current International
Class: |
A61B
5/08 (20060101); A61B 10/00 (20060101); B65D
81/00 (20060101) |
Field of
Search: |
;600/562,529,543,532 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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19619763 |
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Nov 1997 |
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DE |
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2012068374 |
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May 2012 |
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WO |
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Other References
International Search Report for International Application No.
PCT/US2009/068961, mailed Aug. 25, 2010. cited by applicant .
International Preliminary Report on Patentability for International
Application No. PCT/US2009/068961, dated Jun. 29, 2011. cited by
applicant .
Notification of Transmittal of the International Search Report and
the Written Opinion of the International Searching Authority, or
the Declaration for International Application No.
PCT/US2011/061187, mailed Jun. 29, 2012. cited by applicant .
Supplementary European Search Report, dated Jan. 9, 2014, received
in connection with European Application No. 09835693.4. cited by
applicant.
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Primary Examiner: Towa; Rene
Assistant Examiner: Abouelela; May
Attorney, Agent or Firm: Meunier Carlin & Curfman,
LLC
Government Interests
GOVERNMENT INTEREST
This invention was made at Georgia Institute of Technology and the
Centers for Disease Control and Prevention. Therefore, the United
States Government has certain rights in this invention.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. Provisional Application
No: 61/140,292 filed Dec. 23, 2008, the entire contents of which
are incorporated herein by reference.
Claims
The invention claimed is:
1. A process of sampling aerosolized lung material comprising:
providing a collection device comprising a conduit having a first
open end and a second end, said conduit connected to a filter;
separating upper airway fluid from aerosolized lung material lower
airway fluid by inserting said first open end of said collection
device a distance posterior to at least one tooth of a subject,
wherein the first open end is located in the oral cavity of the
subject, and sampling the aerosolized lung material by passing the
aerosolized lung material through said conduit, while the first
open end is located in the oral cavity of the subject, said
aerosolized lung material lower airway fluid traversing said filter
to trap aerosolized material in said filter.
2. The process of claim 1 wherein said distance is 5 millimeters or
more posterior to at least one tooth of the subject.
3. The process of claim 1 wherein said distance is between 5 and 80
millimeters posterior to at least one tooth of the subject.
4. The process of claim 1 wherein said distance is from 20 to 30
millimeters posterior to at least one tooth of the subject.
5. The process of claim 1 wherein said device further comprises an
identifiable position on said conduit between said first open end
and said second end, said position defining said distance during
collection of aerosolized material from a lung.
6. The process of claim 1 wherein said device further comprises a
shaft fluidly connected to said conduit; at least a portion of said
shaft between said conduit and said filter.
7. The process of claim 1 wherein said device further comprises a
chamber fluidly connected to said conduit at said second end.
8. A process of discriminatorily sampling lower airway material
comprising: providing a collection device comprising a conduit
having a first open end and a second end, said conduit connected to
a sampling apparatus; separating upper airway fluid from lower
airway aerosolized material by inserting said first open end of
said collection device a distance posterior to at least one tooth
of a subject, wherein the first open end is located in the oral
cavity of the subject; and contacting said lower airway aerosolized
material with said sampling apparatus to sample the aerosolized
lung material by passing the aerosolized lung material through said
conduit, while the first open end is located in the oral cavity of
the subject.
9. The process of claim 8 wherein said sampling apparatus is a
filter or a detector.
10. The process of claim 8 wherein said distance is greater than 5
millimeters posterior to at least one tooth of the subject.
11. The process of claim 8 wherein said distance is between 5 and
80 millimeters posterior to at least one tooth of the subject.
12. The process of claim 8 wherein said distance is between 20 and
30 millimeters posterior to at least one tooth of the subject.
13. The process of claim 8 wherein said material is an analyte.
14. The process of claim 13 further comprising: detecting the
presence or absence of said analyte interacting with said sampling
apparatus.
Description
FIELD OF THE INVENTION
The invention relates to sampling exhaled air. More specifically
the invention relates to collection of materials such as pathogens
from alveolar aerosols or other lower respiratory aerosols to the
exclusion of significant contamination by upper respiratory
materials such as solid and liquid pathogens contained therein.
BACKGROUND OF THE INVENTION
Pneumonia, or an inflammation of the lungs, is a leading cause of
morbidity and mortality worldwide. In 2002, there were 451 million
lower respiratory infections reported to the World Health
Organization. Worldwide, pneumonia accounts for nearly 30% of all
deaths in children under the age of five, killing more children
than AIDS, malaria, and measles combined. In the United States,
there were an estimated 1.4 million hospitalizations and 59,000
deaths due to pneumonia in 2002. Pneumonia can be caused by a
variety of bacterial and viral pathogens, including streptococcus
pneumoniae, mycoplasma tuberculosis, influenza viruses, respiratory
syncytial virus, parainfluenza, adenovirus, rhinovirus, human
bocavirus, influenza, Mycoplasma pneumoniae, hantavirus, and
cytomegalovirus.
To treat this condition appropriately it is necessary to properly
identify the pathogen in the lower airway. This can be done by
checking for the presence of the pathogen, virus, bacteria or
fungus, in the lung, i.e. alveoli and/or bronchioles. Obtaining a
sample from the lung and confirming the etiology of pneumonia has
proven difficult. For example, in the case of one of the leading
causes of pneumonia, streptococcus pneumonia, as much as 70% of
healthy people carry pneumococcus in their upper respiratory
system. This makes it difficult with the usual method of specimen
collection, a sputum specimen, to confidently determine if a
positive detection for S. Pneumoniae indicates carriage or the
cause of pneumonia. A sputum specimen is collected after passing
through the upper respiratory tract and mouth and is, therefore,
contaminated with upper respiratory tract organisms. More invasive
techniques including bronchial lavage, laparoscopic alveolar
biopsy, or pleural tap do indicate presence of an organism in the
lung but carry greater risk to the patient and are costly and
painful.
An easy to obtain sample of material from the diseased lung would
greatly improve a physician's ability to diagnose and treat
pneumonia. A sample of material from lung alveoli and bronchioles
is also beneficial in various other situations such as determining
the presence and concentration of alcohol in the blood stream and
diagnosing disease processes such as lung cancer.
Accurate diagnosis of pneumonia is still a major problem and the
field is innovating toward complex devices with multiple valves and
chambers. There is an unmet need for a simple device for collecting
a sufficient sample of lower airway material not contaminated by
upper airway material for accurate detection clinical of pneumonia.
Thus, there exists a need for a simple device and process for
collection of lower respiratory air such as lung aerosols while
minimizing or eliminating contaminating upper respiratory tract air
from the sample. There further exists a need for a device that can
collect materials such as pathogenic organisms from lower
respiratory tract air without significant contamination from
similar or identical organisms in the upper respiratory tract.
SUMMARY OF THE INVENTION
A lower respiratory aerosol sample collection device is provided
that is simple, inexpensive, and accurate for the collection of
aerosols from the alveoli and bronchioles of the lung while
excluding contaminating material from the upper airway. The
inventive device functions without the need for complex valving,
switching, or actual collection of air from the lower respiratory
system. The inventive device does not require: electronic
detection, collection, or measuring devices; chamber(s); resistance
elements or shapes; or particular positioning. The inventive
collection device also allows a sample of lower airway material
from multiple exhalations to be obtained without the need for
significant resetting of the device or collection of the air from a
prior breath.
An inventive device is optionally 50 percent or more effective at
separating lower airway aerosols from upper airway material. More
preferably, a device is 50-100 percent effective. Optionally, a
device is 50, 60, 70, 80, or 90+ percent effective. Preferably, an
inventive device is effective in a position with a shaft in a
vertical orientation or 90 degrees either direction. Optionally, a
shaft is in a lower position and the device will separate lower
airway aerosols.
An inventive lung aerosol separation and collection device includes
a conduit into which a patient or other subject exhales or coughs
via a first open end. A conduit optionally includes a narrowed
section or Venturi channel whereby the exhaled fluid passes. The
breath travels through the conduit which is connected to a shaft
that preferably has higher flow resistance than a second open end.
The conduit is also fluidly connected to a chamber that serves to
collect the upper airway air. As the upper airway air is expelled
first during exhalation, the conduit fills to a predetermined
volume. When full, the force of the full chamber allows the
following lower airway air to be directed to the shaft and through
the filter. It is preferred that the size of the chamber be less
than 500 ml. The shaft is connected to a filter that lower airway
air flows through. The filter functions to collect sample material
from the lower airway air as it passes through. Target material
such as bacteria, viruses, fungus, or other cellular or target
materials are trapped in the filter while remaining lower airway
air passes through the system.
An inventive device optionally includes a trap to collect liquid
material that may contaminate the filter or does not represent the
aerosolized target material of interest. A trap is preferably
positioned at a region of the conduit that is substantially
opposite the shaft.
An optional valve is present in the shaft or connected to the shaft
whereby a force closes the valve prior to filling the chamber. The
valve is preferably positioned in the shaft between the filter and
the conduit. A valve is optionally a check valve, a quarter turn
valve, diaphragm valve, globe valve, or other valve known in the
art. Preferably, a valve is a check valve. Several types of check
valves are operable illustratively including a ball, swing,
clapper, stop, or a lift check valve. Most preferably, a check
valve is a ball-check valve.
Optionally, a conduit includes a narrowed section or Venturi
channel whereby the exhaled fluid passes. An inventive device
preferably functions by creating a negative flow in the shaft
during the initial phase of exhalation where upper airway air is
first expelled. This negative pressure can passively force the
valve into a closed position by fluid passing through the narrow
region of the conduit.
A preferred conduit has a curvilinear upper surface continuous with
a lower surface that extends between a first end and a second end
of the conduit. It is preferred that the shaft be connected to the
conduit in at the upper surface.
To direct proper positioning of the device in the oral cavity of a
subject, one or more ridges are present on the conduit. Optionally,
a first ridge is present in the upper surface and a second ridge is
present in the lower surface. The ridges are optionally offset in
distance from the first end. In one embodiment, a ridge is from
5-35 mm from the first end of the conduit. Preferably the ridge is
greater than 10 mm from the first end of the conduit.
An inventive device also optionally includes a trap. A trap is
preferably located on the lower surface. It is preferred that the
lower surface at the trap is below the lower surface at the first
end and the lower surface at the narrow region during operation.
This forms a depression in the device that serves to trap unwanted
liquids from passing into the narrow region.
A capacitive chamber is optionally present located between the
filter and the conduit.
In addition to an open first end, an inventive device optionally
includes a mouthpiece located at the first end. The mouthpiece
optionally has a narrow cross sectional region and a wide cross
sectional region and is connected to the first end at the wide
region of the mouthpiece.
An inventive process of collecting a sample from lung aerosols is
provided. The inventive process includes separating lung aerosols
from upper airway air by passing the lung aerosols through a filter
not exposed to upper airway air and collecting a sample from the
filter. The inventive process also optionally includes collecting
sample from a second breath of a subject by passing lung aerosols
from the second breath through the filter. Optionally, lung
aerosols from multiple breaths is passed through the filter.
Optionally, an inventive process includes collecting or sampling
upper airway air that is separated from lower lung aerosols.
A process of detecting or diagnosing a disease is also provided. A
disease is optionally an infectious disease or a non-infectious
disease illustratively cancer. The process includes separating lung
aerosols from upper airway air and passing the lung aerosols
through a filter not exposed to upper airway air. The process
further includes collecting separated upper airway air and
detecting the presence or absence of a pathogen in the lung
aerosols and the upper airway air to diagnose the presence of a
disease in the subject.
A process of detecting the presence or concentration of an analyte
is also provided. The process includes separating lung aerosols
from upper airway air and exposing the lung aerosols to a detector
not exposed to upper airway air and detecting the presence or
absence of an analyte in the lung aerosols. The process optionally
further includes exposing upper airway air to a second detector and
detecting the presence or absence of an analyte in the upper airway
air.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents a preferred embodiment of the device;
FIG. 2 represents two perspectives on the inventive conduit and
shaft of a preferred embodiment of the inventive device;
FIG. 3 represents an alternative embodiment of the inventive
device;
FIG. 4 represents a schematic of an analyte detection embodiment of
the inventive device;
FIG. 5 represents a preferred embodiment of an inventive
device;
FIG. 6 represents the oxygen levels in upper airway air or lower
airway air as obtained by the inventive device.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It is to be understood that the present invention is not limited to
particular embodiments described, which may, of course, vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular embodiments only and is not
intended to be limiting.
The invention has utility for the collection of lower respiratory
tract air. The invention has further utility as a diagnostic aid
for the detection and diagnosis of disease or abnormality. As the
device is able to readily distinguish between the contents of the
lower respiratory tract and the upper respiratory tract, the device
is operable for detecting the presence of alcohol in the blood
independent of recent consumption and contamination by residuary
alcohol in the mouth or upper digestive tract.
The invention provides a segregated sampling of the aerosolized
material from the lower airway through the combination of a single
flexible chamber and separate sampling apparatus while minimizing
the amount of contaminants from saliva and mucus collected from the
oropharyngeal cavity. The device requires no power, active valves,
or secondary apparatus.
The invention provides for the diagnosis of infectious pneumonia
that is simple and inexpensive. The device segregates lower
respiratory gas and aerosolized material from contaminants such as
liquid from the mouth and gas or aerosolized pathogens from the
oral cavity. Illustratively, a filter traps the lung pathogens
without a complicating second chamber. The outflow tract through
the filter provides for low resistance and variable breath volumes.
A simple fluid dynamics Venturi pressure system maintains
segregation of gases during exhalation. A shaped mouthpiece
effectively prevents large amounts of oral liquids from entering
the device. An air-liquid trap uses gas diversion to further reduce
liquid contamination. An elastic chamber of variable volume is
optionally adjusted to the lung volume of individual patients such
as a child with reduced lung volume or an adult with higher lung
volume. Pathogens detectable or collectable by the inventive device
optionally include, but are not limited to, Streptococcus
Pneumonia, H. influenza, M. Tuberculosis, viruses, and fungi.
Analytes detectable or collectible by the inventive device
illustratively include: cells such as normal cells or abnormal
cells illustratively including cancer cells; proteins
illustratively including amylase; nucleic acids such as DNA or RNA;
cytokines; chemokines; nitrogen oxide(s); carbon dioxide; acetone;
alcohol including ethanol; glucose, or other sugars; and
surfactant. An analyte is optionally a blood analyte. A blood
analyte is preferably a molecule that is present in the bloodstream
of a subject and is detectable in lung fluid. Illustratively, the
amount of alcohol and acetone, as two examples of an analyte, in a
sample of lung aerosols will allow computation of total body fat as
described in U.S. Pat. No. 4,114,422, the contents of which are
incorporated herein by reference.
The inventive device has any number of clinical uses in
interrogating the respiratory system. Pathogens causing pneumonia
of the lower airway are preferably sampled using the device.
Exhaled ethanol from the bloodstream is optionally sampled more
accurately using the device than is achieved using prior art
devices. Inspired samples of asbestos or coal are also optionally
sampled to differentiate upper and lower airway origins. Cancer
cells from the lower airway are differentiable from such cells
present in upper airway origins. Oxygen in gas may need to be
measured separately from oxygen in the liquid material in the upper
airway.
As used herein the word "fluid" is defined as a non-solid
substance. In a preferred embodiment a fluid is a gaseous
substance. Illustratively a gas substance is air. Air is preferably
air exhaled from a subject into the inventive device for separation
and collection of material contained in the fluid. More preferably,
air is coughed from a subject into the inventive device for
separation and collection of lower airway aerosols.
As used herein the term "upper airway" air is defined as the air
present in the oral cavity as the region external to the
epiglottis. The volume of this air is dependent on the size of the
subject. For a child the volume of upper airway air may be as
little as 50 ml. For a large adult the volume may be as much as 300
ml. Typically, an average adult will expel upper airway air in the
first 100 to 150 ml of exhaled breath.
As used herein the term "lower airway" air refers to air contained
in the lungs, including bronchioles, alveolar sacs and alveoli when
a subject has inhaled. The lower airway includes all anatomical
structures internal to the epiglottis.
As used herein the term "alveolar air" is used synonymously with
lower airway air and includes air present in the lungs prior to
exhaling including that from the alveoli, bronchioles, and other
lung passages.
As used herein the term "lung aerosols" means any material
aerosolized in fluid from the lower airway.
It is appreciated that the inventive device operates without active
or electronically controlled valves, colorimetric or other specific
indicators, pistons, multiple collection or diversion chambers,
condenser tubes, heating or cooling mechanisms. In a preferred
embodiment an inventive device samples material in lung aerosols
without collection of the air itself or sampling of the lung
aerosols.
Referring to FIG. 1, an inventive device 101 includes a conduit 103
with a first end 105 and a second end 107. Fluid 104 passes through
said conduit 103. The conduit is preferably used in a substantially
horizontal orientation with respect to the elevation of the first
end 105 and the second end 107. The conduit is optionally made from
polymeric material, metal, glass, and the like.
In the pictured embodiment of FIG. 1, the conduit 103 is
substantially linear so as to form a cylindrical cross sectional
area. It is appreciated that the cross sectional area of the
internal space of the conduit 103 need not be circular. The cross
sectional area is optionally oblong, square, rectangular,
triangular, irregular, or any other shape. The conduit 103 is
optionally non-linear from the first end 105 to the second end 107.
Preferably, the fluid path from the first end 105 through the
device is not linear and has one or more bends so that particles
with more density will impinge on the wall of the conduit lumen.
The bend(s) causes particles with greater mass and momentum to hit
the wall of the conduit 103, whereas lighter aerosolized particles
will more easily pass therethrough. It is appreciated that relative
sizing of the cross sectional areas of the ends 105, 107 to a
narrowed internal region therebetween allows one to select the
particle fraction such as an aerosol size for separation.
A conduit 103 has a curvilinear upper surface continuous with a
curvilinear lower surface. The curvilinear shapes of the upper
surface and lower surface are optionally correlated or identical or
are optionally independent such that the internal dimensions of the
conduit 103 are not constant between the first end 105 and the
second end 107.
The conduit 103 is fluidly connected to a shaft 115. The shaft 115
preferably extends perpendicularly from the conduit 103.
Optionally, the shaft 115 extends at an angle from the central axis
of the conduit 103. The shaft 115 is preferably integral with the
conduit 103. The shaft 115 is preferably made from the same
material as the conduit 103 so as to form a single unified piece.
The shaft 115 preferably bridges the conduit 103 to a sampling
apparatus 117.
In one embodiment, the shaft 115 is spatially offset relative to a
central axis of the conduit 103. FIG. 1 depicts an elevated offset
in a preferred embodiment. This offset directs the denser liquid
material away from the shaft 115 and into a trap 119 or other lower
region of the conduit 103. The liquid material has a higher density
and momentum than aerosolized particles and tends to travel in a
straight line as fluid moves through the device 101. Thus, the
conduit preferably is oriented in line with the first end 105 while
the shaft 115 preferably extends at an angle from this line.
Preferably, a shaft 115 is located on the upper surface 108 of the
conduit 103.
The shaft 115 optionally incorporates a smaller opening or
overlapping opening to further prevent liquids from entering as
fluid passes through the device 101. A trap 119 is optionally
located between the first end 105 and the shaft 115 on the conduit
103. The conduit 103 preferably forms a depressed shape with lower
elevation with respect to the first end 105 and the shaft 115 so as
to form a trap 119 so that liquid contaminant from the upper airway
is segregated from the aerosolized pathogens or other material
present in the fluid from the lower airway. This prevents the
liquid contaminant from being transported to the distal ends of the
device improving separation of alveolar material.
At the conduit second end 107 is preferably a chamber 125. Chamber
125 has an entrance opening that preferably provides lower flow
resistance than the entrance opening of the first end 105 of the
conduit 103. More preferably, the chamber entrance opening is of
the same cross sectional area as the fourth area 121 of the conduit
103. The differences in flow resistance allows fluid flow to pass
into the chamber 125 before the shaft 115 as flow will follow the
path of least resistance. Fluid will then pass into the chamber 125
filling it. Preferably, the chamber 125 is made from a flexible
material so that the chamber 125 will expand from the presence of
incoming fluid to a maximum internal volume. The maximum internal
volume is defined by the internal area of the chamber 125 and the
elasticity of the chamber material. Preferably, the chamber is made
from material with low elasticity. A chamber 125 is preferably
elastic to provide shock-absorbing compliance during coughing.
Optionally, the chamber 125 is made from material with
substantially no elasticity. The chamber is optionally made from
natural or synthetic materials illustratively including latex,
rubber, polymeric material, glass, metal, and the like.
In an embodiment with a flexible chamber 125, the volume of chamber
125 will increase to a predetermined amount with breath from the
upper airway. After inflation of chamber 125, resistance to further
inflation occurs proving sufficient resistance such that additional
exhaled breath from the lower airway will then pass into the shaft
115. In one embodiment, the aerosol content is filtered for
pathogen directly. In another embodiment, the entire lower airway
breath is collected in a second chamber.
The chamber 125 is preferably a flexible material that can be
collapsed by physical force or expanded by capture of upper
respiratory air. Optionally, a chamber 125 is a solid material such
as glass, metal, rigid polymers and the like.
The average normal (tidal) exhalation in a healthy adult is
approximately 500 ml. Of this 500 ml, the initial 150 ml of exhaled
gas is from the upper airway including the trachea, and
oropharyngeal space. This portion of gas is commonly referred to as
the "dead space" since it does not contribute to oxygen refreshment
to the lungs. The latter 350+ ml of exhaled gas comes from the
lower respiratory airway and alveoli. Thus, chamber 125 preferably
expands to 150 ml and then provides resistance to further
inflation. The lower airway breath of 350 ml is then diverted into
the shaft 115. By separating the initial 150 ml from the 500 ml
sample, it is possible to isolate the contaminating bacteria in the
first 150 ml from the true pneumonia pathogens present the alveolar
space contained in the subsequently exhaled 350 ml of air.
A chamber 125 is preferably of sufficient internal volume to
capture all upper respiratory air. Preferably, a chamber 125 has an
internal volume of less than 300 ml. Optionally, a chamber has a
volume between 25 ml and 300 ml. More preferably, a chamber has an
internal volume between 50 and 150 ml. Most preferably, a chamber
has an internal volume of 100-150 ml.
The chamber 125 is optionally adjusted or replaced with a different
size chamber to collect different volumes depending on the size of
the patient. For instance, a child may require the chamber to
collect a volume of only 50 ml, while a large adult may require
collection of 300 ml.
A shaft 115 preferably terminates in or includes a sampling
apparatus 117. A sampling apparatus 117 is optionally a detector or
a filter. In a preferred embodiment a sampling apparatus 117 is a
filter. A filter is preferably of any suitable material to allow
gaseous fluid to pass through the filter while trapping materials
contained in the fluid such as pathogens including virus particles,
bacteria, yeast, fungus, and the like. A filter optionally traps
environmental contaminants such as asbestos, fiberglass, pesticides
and the like. A filter is optionally made from paper, gelatin,
polymers, glass, or other material. The material is preferably
operable for collecting target material. Optionally, a filter is
sized so as to collect some targeted materials while letting others
pass thorough. Illustratively, a filter is used to trap bacteria.
Optionally, bacteria is S. pneumonia. Optionally, a filter will
trap virus particles. Optionally, a filter is made of reactive
material that will interact with a target molecule or pathogen
thereby trapping the molecule or pathogen in the filter while
selectively allowing non-targets to pass through the filter. In one
embodiment a filter is less than 100% effective at trapping a
target. Filter materials suitable for use with the inventive device
are known in the art and are obtained from sources known in the
art, illustratively, 3M Corp. (St. Paul, Minn.). In a preferred
embodiment the VBMax filters from A-M Systems, Inc. (Carlsborg,
Wash.) are used.
A filter will preferably allow the velocity and volume of lower
airway fluid associated with a cough to readily pass though the
filter without significant resistance so material from the coughed
lower airway fluid can be readily collected on the filter. Without
significant resistance is preferably no more resistance than
necessary to trap desired material on or in the filter. It is
preferred that the device provide minimal resistance to lower
airway fluid passing through the shaft to contact a detection
apparatus.
Fluid is optionally exhaled fluid from a subject, fluid exhaled
during a cough, or a rapid forced exhalation.
In one embodiment a filter is present in a cartridge that attaches
to a shaft 115. Optionally, the filter cartridge 127 attaches to a
shaft 115 by way of a press fit. Optionally, a filter cartridge 127
attaches to a shaft 115 by a screw fit, clamp, intermediate
connector, or other type of fitting known in the art.
An inventive device optionally includes a valve 129 between the
sampling apparatus 117 and the conduit 103. A valve 129 is
preferably housed within a shaft 115. It is appreciated that a
valve is optionally placed between the shaft 115 and the conduit
103, or between the shaft 115 and the sampling apparatus 117, or
filter cartridge 127. A valve preferably will close the internal
area of the shaft 115 reducing or eliminating fluid flow from the
conduit 103 to the shaft 115. A valve is optionally a check valve,
a ball valve, a diaphragm valve, a globe valve, and the like.
Preferably, a valve is a check valve. Types of check valves
illustratively include a ball, diaphragm, swing, clapper,
stop-check, lift-check, and the like. In a preferred embodiment a
valve is a ball-check valve. A valve is preferably a passive valve
such that user input other than exhaling or coughing is not
required for proper operation of the device.
An inventive device optionally includes a mouthpiece 137 located at
the first end 105. A mouthpiece 137 is optionally a tapered shape
whereby the taper is preferably not constant. The tapered shape
produces a narrow region 143 and a wide region 145. The mouthpiece
137 preferably extends posterior to the teeth of a subject during
exhalation. This extension prevents saliva and other mouth contents
from entering the device. The extension also reduces the amount of
upper airway material entering the collection device. Preferably,
the mouthpiece 137 has an opening entrance at the proximal end
which is located posterior to the teeth of a subject during
exhalation. More preferably, the entrance is more than 10 mm
posterior to the teeth. The mouthpiece optionally a round, oval,
square, or rectangular opening. In a preferred embodiment the
proximal opening of the mouthpiece is smaller in cross sectional
area than the exit to the conduit 103. This mouthpiece
configuration prevents unwanted upper airway and oral cavity
material from entering the collection device during use. By
positioning the entrance of the device appropriately, the liquid
saliva and sputum does not enter the device in large amounts.
Mouthpieces of different size entrance openings are optionally
utilized for patients of different size for collecting coughs
versus deep breath exhalation. A one-way valve is optionally
included in the mouthpiece 137 to prevent backflow.
Referring to FIG. 2 maintaining like numerals, a shaft 215 is
preferably located at the narrowed region ("Venturi channel") 223
of the conduit 203. Without being limited to one operational
mechanism, the increased fluid flow rate through the Venturi
channel 223 causes a negative pressure within the shaft 215. The
negative pressure brings the valve 229 into a closed position,
thus, preventing fluid from entering the shaft prior to full
inflation of the chamber 225. It is appreciated that this negative
pressure is present independent of the presence of a valve in the
shaft such that fluid is prevented from entering the shaft prior to
chamber inflation simply due to the increased fluid flow rate in
the Venturi channel 223 of the conduit 203. As such, the valve is
optional, yet preferred.
An inventive conduit optionally has a first cross sectional area
209 defined as the internal cross sectional area at the first end
205. A cross sectional second area 211 is the internal cross
sectional area at a point some distance toward the second end 207.
Preferably, the first cross sectional area 209 is larger than the
second cross sectional area 211. Optionally, the first cross
sectional area 209 is the same as the second cross sectional area
211. It is appreciated that a first cross sectional area 209 is
optionally smaller than a second cross sectional area 211. A third
cross sectional area 213 is defined as an internal cross sectional
area at a location in the conduit 203 intermediate of the first
cross sectional area 209 and the second cross sectional area
211.
A preferred embodiment includes a conduit with a fourth area 221.
Preferably, the second area 211 is smaller than the third area 213
and the fourth area 221. This forces the fluid into an area of
lower cross sectional area forming a Venturi channel 223. The
Venturi channel is a narrowed flow section that causes higher fluid
velocity and consequently, lower dynamic pressure through the flow
section. This creates a negative pressure in the shaft 215 during
movement of upper airway fluid through the conduit 203. The Venturi
channel 223 will prevent fluid motion toward the filter 217 during
the first part of exhalation when upper airway fluid is passing
thorough the device.
A conduit 203 preferably includes one or more positions 206
defining a distance from the teeth of a subject to the first end of
the device when the device is used in the mouth of a subject. A
position 206 is optionally an identifiable region on the conduit
that a user or administrator locates to associate the teeth of a
user for proper positioning of the device. A position 206 is
optionally greater than 10 millimeters from the first end.
Optionally, a position 206 is 10 to 80 millimeters from the first
end. In a most preferred embodiment, a position 206 is from 20 to
30 millimeters from the first end. A position 206 is optionally one
or more locations such as a line, color change, ridge, channel,
depression, joint, or other visual, tactile, auditory, or
measurably identifiable location.
In a preferred embodiment a position is defined by one or more
ridges. A ridge is preferably dimensioned so that a subject's teeth
will engage the ridge during exhalation. A first ridge 231 is
preferably located on the upper surface 208 of the conduit 203. A
second ridge 233 is located on the lower surface 210 of the conduit
203. The ridges optionally define a region of increased outer
circumference. Located toward the first end 205 on the conduit 203
is optionally a channel 235 that acts as a position. During
operation a user fits his teeth within the channel at the point of
the ridges. This helps define the location of the device in the
oral cavity. Preferably, the ridges 231, 233 are between 5 and 80
mm from the first end 205. More preferably, the ridges 231,233 are
greater than 10 mm from the first end 205. Most preferably, the
ridges 231, 233 are 25 mm from the first end 205. Optionally, the
first ridge 231 is positioned further from the first end 205 than
the second ridge 233. This offset orientation comfortably
accommodates a natural overbite of a user. Optionally, a first
ridge 231 is positioned nearer to the first end 205 than the second
ridge 233.
A trap 219 is positioned between the narrow region 223 and the
ridges 231, 233. This trap 219 defines a region in the lower
surface 210 of the conduit 203 below the lower surface at the first
end 205 and below the lower surface at the narrow region 223. This
configuration collects unwanted liquid as the fluid passes from the
first end toward the narrow region due to the curvilinear shape of
the conduit 203.
Referring to FIG. 3, an inventive collection device optionally
includes a second chamber such as a capacitive chamber 339 located
between the conduit 303 and the shaft 315. A capacitive chamber 339
operates to absorb the high pressure/volume of a cough that can be
slowly bled out to the chamber 325 without allowing upper airway
air to enter the filter. A capacitive chamber 339 is optionally an
enlargement of the shaft 315 or is a pliable section that will
expand in the presence of a rapid increase in pressure/volume due
to a cough. The patient may be asked to inhale deeply and cough to
expel more contents from the alveoli. The device can accommodate
high pressures generated by such a cough and still segregate the
lower airway material.
As illustrated in FIG. 4, in one embodiment a sampling apparatus is
one or more detectors 441. A detector 441 is optionally positioned
in a shaft 415 so that lower airway/lung aerosols is exposed to a
detector during an exhalation of a subject. Optionally, a second
detector is present within the conduit 403. The second detector is
preferably located distally from the shaft within the conduit 403
or within the chamber 425 so that it is not exposed to lower airway
air and is used to detect the presence of a target in the upper
airway. A detector is optionally operable to detect the presence or
absence of a bacteria, virus, fungus, antibody, protein, or
chemical such as carbon dioxide, carbon monoxide, nitric oxide,
alcohol and the like. In one embodiment a detector is capable of
detecting the presence of alcohol in the lower or upper airway of a
subject. A detector is optionally a surface, a labyrinth, a trap,
sticky substance, warmed or cold surface, metal, or electrical,
chemical or mechanical sensor. A sensor or other detector is
illustratively operable to detect a molecule or pathogen, either by
color, optical, or electronic or other chemical means.
One or more parts of an inventive device are optionally reusable.
Illustratively, a conduit is sterilizable such as by autoclaving
for reuse to reduce possibility of contamination from a prior use.
Optionally, the conduit and shaft are reusable. Optionally, the
entire device is reusable.
While the inventive device is preferably used with the first end
positioned posterior to the front teeth, it is appreciated that the
device is similarly functional positioned near, at, or in front of
the teeth.
A process is provided for detecting the presence or absence of
material from the lower airway as exhaled, preferably by coughing,
by a subject to the exclusion of material from the upper airway. An
inventive process illustratively includes separating lung aerosols
from upper airway air using an inventive device; contacting the
lung aerosols with one or more sampling apparatuses, optionally
excluding upper airway air from contacting a sampling apparatus,
and optionally collecting a sample on the sampling apparatus.
An inventive process optionally includes separating lung aerosols
from a second breath. A breath as used herein is a single round of
respiration including inhaling and exhaling. Exhaling preferably
includes one or more coughs. Collecting material from a cough or
multiple coughs is most preferred. The inventive device is operable
for separating lung aerosols from as many breaths as is desired to
improve detection of target material. As the exit of the shaft
preferably freely dispels air, as much air as is desired is
optionally passed through the filter by way of collection of
several successive exhalations. The device preferably does not
require collection of the lower airway air for reuse or sampling.
The inventive process preferably collects aerosols from two exhaled
breaths. Optionally, the inventive process includes collection of
multiple breaths. Multiple breaths is optionally two, three, four,
five, six, seven, eight, nine, ten, or more breaths. It is
appreciated that the device is not limited to any number of
breaths.
An inventive process optionally includes collecting the upper
airway fluid. Upper airway aerosols or liquid are optionally
collected by removing the material trapped in the chamber or in the
conduit following an exhaled breath. A chamber optionally has a
valve or other collection opening to facilitate collection of upper
airway material. The upper airway aerosol is optionally sampled. A
second filter, detector, or sensor is optionally present within or
at an exit portion of a chamber, in the conduit, or in the chamber
for collection of the aerosols. A one-way valve is optionally
present in the conduit preferably positioned toward the second end
such that upper airway air may freely flow into the chamber until
maximal expansion. After the exhalation is complete a user
optionally collapses a chamber optionally forcing collected upper
airway air through a second sampling apparatus capturing, sensing,
or detecting upper airway material without forcing this material
back into the conduit preventing possible contamination of the
filter in the shaft.
Detection of material from either the upper airway or the lower
airway is optionally by polymerase chain reaction (PCR), real-time
PCR, reverse-transcription PCR, enzyme linked immunosorbant assay
(ELISA), mass spectrometry, liquid chromatography, Southern
blotting, western blotting, northern blotting, enzymatic assay,
culturing, cell infection, other assays known in the art, or
combinations thereof to selectively amplify or identify material
from either lower airway aerosols or upper airway liquid or
aerosols. The aforementioned detection or identification methods
are generally known to those of skill in the art and are described
in detail in methodology treatises such as Molecular Cloning: A
Laboratory Manual, 2nd ed., vol. 1-3, ed. Sambrook et al., Cold
Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and
Current Protocols in Molecular Biology, ed. Ausubel et al., Greene
Publishing and Wiley-Interscience, New York, 1992 (with periodic
updates). Immunological methods (e.g., preparation of
antigen-specific antibodies, immunoprecipitation, and
immunoblotting) are described, e.g., in Current Protocols in
Immunology, ed. Coligan et al., John Wiley & Sons, New York,
1991; and Methods of Immunological Analysis, ed. Masseyeff et al.,
John Wiley & Sons, New York, 1992; among others. The contents
of each of which are incorporated herein by reference.
A process of diagnosing a disease is presented including separating
lung aerosols from upper airway aerosols by passing the lung
aerosols through a filter and excluding upper airway aerosols;
collecting the upper airway material; and detecting the presence or
absence of a pathogen, disease cell, protein, or other target in
the lung aerosols or upper airway. A disease is optionally
diagnosed by detecting a target. Illustratively, a disease is
cancer. A user optionally diagnoses the presence of cancer cells by
location to either the lower airway or the upper airway.
A process for detecting an analyte in the blood stream of a subject
is provided. The inventive process includes separating lung
aerosols from upper airway aerosols by a subject exhaling; and
detecting the presence or absence of an analyte on a filter or
detector present in lower airway aerosols.
Various aspects of the present invention are illustrated by the
following non-limiting examples. The examples are for illustrative
purposes and are not a limitation on any practice of the present
invention. It will be understood that variations and modifications
can be made without departing from the spirit and scope of the
invention.
Example 1
A breath separation and collection device is depicted in FIG. 5.
The device includes a single piece conduit and shaft substantially
as depicted in FIG. 2. A ball-check valve is present in the shaft.
A filter is connected to the shaft and housed in a filter
cartridge. A flexible chamber is attached to the second end of the
conduit.
Human subjects (patients) are sampled as approved by Georgia
Institute of Technology Institution Review Board as IRB Protocol
H08353. Patients are asked to expel a deep cough into the device
and continue exhaling residual air in the lungs. Coughing and
sneezing aerosolize a greater number of lower lung pathogens as
compared to exhalation alone.
Example 2
Oxygen Separation Test: Oxygen absorption by blood occurs only in
the lower airway (alveoli), and not in the upper airway (mouth,
trachea). Thus the oxygen level in the lower airway is expected to
be less than that of the upper airway. Ambient atmosphere contains
approximately 21% oxygen, while expired air is about 16.5% oxygen.
The oxygen content from the upper airway chamber is tested and
compared with a sample from a collection chamber located on a
shaft. The percentage of oxygen in each sample is measured with an
oxygen meter (Teledyne Analytical Instruments, Model # GB 300). The
experiment is repeated using the device of Example 1 ten times with
statistical significance defined at the p<0.05 level.
As depicted in FIG. 6, the average percentage of oxygen in lower
airway sample as passed through the filter is 15.9%, whereas the
average upper airway sample is 18.4%. The average percentage of the
room air oxygen as breathed by the patients is 20.9%. The lower
airway sample is statistically lower than the upper airway sample
or the room air with a p-value of <0.0001, n=10. These data
indicate that the inventive device successfully separates lower
airway air from upper airway air.
A second test variation is performed to assess the function of the
ball valve. The Oxygen Separation Test is performed without the
ball valve to determine the effect of the ball valve on the
separation of lower airway samples from upper airway oxygen
content. In the absence of the ball portion of the ball-check
valve, the average percentage of oxygen in the lower airway sample
is 16.9% compared to the upper airway sample of 18.9%
(p<0.0001). The average percentage of oxygen in the lower airway
sample with the ball valve is 15.9% and without the ball valve is
16.9% (p<0.0001).
Example 3
Detection of blood ethanol in lower-respiratory air. Ingested
ethanol appears 20 minutes later in the blood stream and becomes
volatile in the alveolar space, not in the upper airway. Two 0.02%
breath alcohol testers (Advanced Safety Devices) are connected to
the inventive device. One detector samples lower airway air and is
connected to the shaft. The second detector is positioned within
the chamber. Participants drink 50 proof alcohol, 60 ml for females
and 80 ml for males. Participants then rinse the mouth with water
but are not allowed to swallow the water. After 20 minutes, the
participant drinks an 8 oz glass of water and then deep coughs and
exhales residual air into the inventive device as described in
Example 1. The color changing crystals are allowed to develop for 2
minutes. The paired breath alcohol testers are photographed and
resulting color analyzed with photo editing software and the
quantitative saturation and blue levels are measured.
As a control, the volume of lower airway aerosols is directed into
the chamber and thus, through the second detector. The participant
coughs and exhales residual air into the device. After 2 minutes,
the breath alcohol tester with restricted volume is photographed
and analyzed.
In all cases, the lower airway samples change color, whereas the
upper airway samples do not. The differences results in p-values as
follows: saturation--p=0.0015; and blue--p=0.0019. As a control,
the chamber volume is separately tested to assure that this volume
was enough to convert the colorimetric crystals. Since these three
values of the alcohol crystals are significantly different the
device successfully samples the volatiles generated in the lower
airway separately from the upper airway.
Example 4
Negative pressure created by a Venturi channel: The filter of the
device of Example 1 is replaced with a thin plastic bag filled with
50 ml of air and the chamber is removed. The direction of flow
through the Venturi is quantified by the time required to deflate a
fixed 50 ml thin bag. With every exhalation, the 50 ml bag attached
to the filter tube fully deflated over an average of 1.25+/-0.25 s.
Table 1 shows the results of the Venturi test illustrating
deflation of the filter bag. Thus, the Venturi creates a negative
pressure in the shaft. The results demonstrate that the device
prevents the initial upper airway gas from passing through the
collection chamber during deep coughing.
TABLE-US-00001 TABLE 1 n Time (s)* 1 1.47 2 0.93 3 1.6 4 1.07 5 1.2
AVERAGE: 1.25 +/- 0.25 *Time to deflate bag over filter while
blowing through device.
Example 5
Proper positioning of the device in the mouth: The device of
Example 1 is tested in the correct position with the teeth in the
channel at the base of the ridge and the first end extending 25 mm
proximal to the teeth for the correct position and compared with an
incorrect position with the opening at the first end of the device
less than 10 mm proximal to the teeth. After deep coughing into the
device, the amount of liquid that enters the device is measured and
recorded for an initial oral volume of volume of 5, 7.5, 10, and 15
ml of water. The experiment is repeated for a total of three
measurements for each initial volume of water.
When the mouthpiece is correctly positioned, no water enters the
device, even when the amount of water starting in the mouth is
increased to 15 ml (Table 2). A significant amount of water enters
the device with incorrect device positioning.
TABLE-US-00002 TABLE 2 Ending Volume in device
(ml).sup..dagger-dbl. Initial Oral Correctly Positioned Incorrectly
Positioned Volume (ml).sup..dagger. Mouthpiece Mouthpiece p-value 5
0 0.8 0.0075* 7.5 0 3.7 0.0142* 10 0 5.5 0.0062* 15 0 7.5 0.0020*
*Statistically significant .sup..dagger.Volume of liquid expelled
into device
The inventive device functions with dramatic angle of positioning
relative to the plane of the face. When the device is placed 45
degrees from the perpendicular to the plane of the face in any
direction no liquid enters the device, as long as the mouthpiece is
positioned correctly with the lips at the ridge on the mouthpiece
and the opening behind the teeth.
Example 6
Phlegm Exclusion Test: A 2.5 ml volume of viscous solid jelly is
used as a surrogate for phlegm in the oral cavity. The participant
coughs into the device with proper and improper mouthpiece
placement. The amount of jelly on the filter of the device of
Example 1 is measured and recorded. This amount is compared to the
control of expectorating the jelly sample directly into a sputum
cup. When the device is correctly positioned no phlegm attaches to
the device filter. In the one trial where jelly was observed on the
filter the amount was less than 1% the starting volume.
Example 7
Collection of liquid in the trap: The device of Example 1 is tested
whereby the volume of material contained in the trap during deep
coughing is measured after successively larger oral volumes of 1,
2, 3, and 4 ml of water is present in the mouth prior to cough. The
experiment is repeated three times. With a starting oral volume of
1 ml of liquid, 0.5 ml of liquid is dispose in the liquid trap
after the deep cough. The results of the Trap Test are shown in
Table 4. The liquid trap effectively captures 0.5 to 0.8 ml of oral
liquids from reaching the outlets of the device during deep
coughing.
TABLE-US-00003 TABLE 4 Oral Volume (ml) Volume Collected in Trap
(ml) 1.0 0.5 2.0 0.6 3.0 0.6 4.0 0.8
Example 8
The device of Example 1 is used with a VBMax filter. A Bacterial
Filtration Efficiency Test and a Viral Filtration Efficiency Test
are performed. Both test procedures are adapted from ASTM F2101.
The bacterial filtration efficiency test uses the challenge
organism Staphylococcus aureus (procedure number STP0009 Rev 02).
The viral filtration efficiency test uses bacteriophage .phi.X174
as the challenge organism.
The average Bacteria Filtration Efficiency is found to be
99.99977%. For the Viral Filtration Efficiency, the average
filtration efficiency is 99.9975% with a mean particle size of 2.8
.mu.m.
Various modifications of the present invention, in addition to
those shown and described herein, will be apparent to those skilled
in the art of the above description. Such modifications are also
intended to fall within the scope of the appended claims.
Patents and publications mentioned in the specification are
indicative of the levels of those skilled in the art to which the
invention pertains. These patents and publications are incorporated
herein by reference to the same extent as if each individual
application or publication was specifically and individually
incorporated herein by reference.
The foregoing description is illustrative of particular embodiments
of the invention, but is not meant to be a limitation upon the
practice thereof. The following claims, including all equivalents
thereof, are intended to define the scope of the invention.
* * * * *